The inhibitory activity of phosphodiesterases (PDEs) consists in the degradation of cyclic nucleotides (cAMP and cGMP) by hydrolysis of the 3′-phosphodiester bond, resulting in the inactive compound 5′-monophosphate. cAMP and cGMP are respectively formed by the adenylate cyclase and guanylate cyclase, acting as second messengers in the intracellular signal transduction. A way to increase intracellular levels of cAMP or cGMP is by PDEs inhibition, since they are their unique degradation pathway. The interest of developing specific PDE inhibitors is based on their anti-inflammatory and immunosuppressive properties shown by agents that can raise intracellular levels of cAMP. Therefore, selective cAMP PDE inhibitors may be interesting as a therapy for the treatment of different diseases [Lugnier, C. Cyclic nucleotide phosphodiesterase (PDE) super family: A new target for the development of specific therapeutic agents. Pharmacol. Ther. 2006, 109, 366-398], mainly immune system alterations, such as multiple sclerosis, inflammatory and also central nervous system (CNS) disorders [Menniti F. S., Faraci W. S., Schmidt C. J. Phosphodiesterases in the CNS: targets for drug development. Nat. Rev. Drug Discov. 2006, 5, 660-670]. Since almost every PDE is expressed in 20CNS, showing in many diseases an increase of function, PDE inhibitors may be also considered as promising drugs for the treatment of psychiatric and neurodegenerative diseases. [Brandon, N. J.; Rotella, D. P. Potencial CNS applications for PDE inhibitors. Ann. Rep. Med. Chem. 2007, 42, 3-12].
As an example, cilostazol, a selective PDE3 inhibitor, has shown to reduce cellular death after stroke (cerebral infarct) and also to promote survival in axotomized ganglion cells of retina. Sildenafil, a PDE5 inhibitor, may improve learning by modulation of NO-cGMP signal transduction, a pathway related to cognitive decline due to age in neurodegenerative diseases. On the other hand, selective PDE10A inhibitors are potent antipsychotic agents able to improve the cognition symptoms of schizophrenia and PDE4 inhibitors represent an interesting approach for the treatment in memory disorders. As an example, Memory Pharmaceuticals is developing a PDE4 inhibitor named MEM 414 for the treatment of Alzheimer's disease (http://www.memorypharma.com/p_MEM1414.html, Exp. Neurol. 2003, 182, 322-334).
Among the 11 PDE isoenzymes identified, PDE7 is specific for cAMP, not affected by Rolipram (PDE4 inhibitor), expressed in different brain areas, as well as in lymphocytes. [Li, L.; Yee, C.; Beavo, J. A. CD3- and CD28-dependent induction of PDE7 required for T cell activation. Science 1999, 283, 848-851; Nakata, A.; Ogawa, K.; Sasaki, T.; Koyama, N.; Wada, K.; Kotera, J.; Kikkawa, H.; Omori, K.; Kaminuma, O. Potential role of PDE7 in human T cell function: comparative effects of two PDE inhibitors. Clin. Exp. Immunol. 2002, 128, 460-466] and its inhibitors have been useful for the study of its physiology and pathology [Martinez, A. PDE7 inhibitors as new drugs for neurological and anti-inflammatory disorders. Exp. Opin. Ther. Patents 2008, 18, 1127-1139]. Thus, it has been shown that the PDE7 selective inhibitor BRL-50481 does not decrease T cell proliferation itself, however it increases synergically the effect of the PDE4 inhibitor Rolipram on the raise of cAMP levels. However, new molecules are needed to validate their pharmacological effects both in vitro and in vivo.
Related to PDE7, it has been reported the use of its inhibitors for the treatment of movement disorders as for example Parkinson's disease. These utilities are described on the patent application WO 2008119057 (Omeros Corporation).